Alzheimer's disease (AD) is a common and devastating neurodegenerative disorder for which no cure exists. Currently available drugs approved by the U.S. FDA typically afford only modest symptomatic benefits. Progressive dementia often results in complete incapacitation, profound impairment in quality of life, enormous burdens on family caregivers and society, and, ultimately, death from one of a variety of complications of the disease.
In the United States alone there are over five million people with AD, a figure that is expected to rise to about 16 million by 2050, with attendant costs exceeding $1.1 trillion dollars. AD is the most frequent reason for nursing home placement and the sixth most common cause of death in the United States. Recent failures of development programs evaluating disease modifying therapies for AD (e.g., solanezumab, an anti-Aβ monoclonal antibody) bring the unmet need for improved therapies into heightened relief.
AD usually presents initially with memory loss, which may be subtle at the onset. Progressive dementia then follows, accompanied by the advent of other cognitive deficits in language (e.g., word-finding difficulties), executive function, and visuospatial recognition. The ability to perform activities of daily living is gradually compromised. Alterations in behavior and personality may take the form of mood fluctuations, apathy, aggression, and loss of inhibition with socially inappropriate behavior. Patients may harbor delusions and experience hallucinations. Ultimately, any semblance of autonomy is completely abolished as patients become bedridden, incontinent, and incapable of feeding, bathing, or dressing themselves. Although the course is variable, AD generally progresses over a period of about a decade. Death commonly results from aspiration pneumonia, inanition, or pulmonary emboli.
The vast majority of AD cases are seen in the elderly, but about 200,000 individuals in the United States younger than 65 years of age are estimated to have the disease. A variety of genetic factors significantly influence susceptibility to disease, most importantly the APOE ε4 allele which, it has been hypothesized, may be associated with impaired clearance of amyloid, which is believed to have a critical role in disease pathogenesis. Aβ42 is thought to represent the toxic and amyloidgenic cleavage product of amyloid precursor protein.
Pathologically, neurodegeneration is prominent in various regions of the temporal lobe, including the entorhinal cortex, hippocampus, and lateral cortex. As the disease becomes more severe, more generalized involvement results in brain shrinkage and ventricular enlargement. Histopathological hallmarks of the disease include neuritic plaques and neurofibrillary tangles. Plaques consist of a dense core containing polymerized amyloid, several other proteins, and proteoglycan, surrounded by dystrophic tau-immunoreactive neurites and activated microglial cells. Neurofibrillary tangles contain abnormally hyperphosphorylated tau protein that can no longer stabilize or interact appropriately with microtubules, or subcellular components that undergird neuronal architecture and that mediate axonal transport of neurotransmitters and ion channels. Impaired cholinergic transmission in AD may be related to degeneration of cholinergic neurons in the nucleus basalis of Meynert that broadly project to the cortex.
All currently approved treatments for AD are associated with only modest benefit. Mean response as measured by ADAS-Cog is approximately 2.7 points for the cholinesterase inhibitors. They may delay, decline, or produce some evidence of improvement in cognition and ability to perform activities of daily living, but treatment has not been shown to permanently halt progression or clearly modify the disease itself.
To a large measure, treatment of patients with AD is supportive, and this entails what often amounts to enormous efforts on the part of family caregivers in the home. The provision of emotional support and supervision, the overseeing of guided activities meant to sustain quality of life and minimize frustration, and assistance, ultimately, with the most basic elements of daily life such as feeding, clothing, and bathing, frequently results in caregiver burnout and nursing home placement as the disease advances toward the terminal stages. The human and economic toll of AD demands improvements in the standard of medical care.
TGF-β1 has been demonstrated to protect neurons against various toxins and injurious agents in cell culture and in vivo. Astroglial over-expression of TGF-β1 in transgenic mice protected against neurodegeneration induced with acute neurotoxin kainic acid or associated with chronic lack of apolipoprotein E expression (Brionne et al., (2003) Neuron 40: 1133-1145). It has been demonstrated that TGF-β1 protects neurons from excitotoxic death (Boche et al., (2003) J. Cereb. Blood Flow Metab. 23: 1174-1182).
Several mechanisms have been postulated to explain how TGF-β1 protects neurons. For example, TGF-β1 decreases Bad, a pro-apoptotic member of the Bcl-2 family, and contributes to the phosphorylation and inactivation, of Bad by activation of the Erk/MAP kinase pathway. TGF-β1, however, also increases production of the anti-apoptotic protein Bcl-2. TGF-β1 has also been shown to synergize with neurotrophins and/or be necessary for at least some of the effects of a number of important growth factors for neurons, including neurotrophins, fibroblast growth factor-2, and glial cell-line derived neurotrophic factor (Unsicker & Krieglstein (2002) Adv. Exp Med. Biol. 513: 353-74; Unsicker & Krieglstein (2000) Cytokine Growth Factor Rev. 11: 97-102). In addition, TGF-β1 increases laminin expression and is necessary for normal laminin protein levels in the brain. It is also possible that TGF-β1 decreases inflammation in the infarction area, attenuating secondary neuronal damage.
TGF-β1 transgenic mice over-expressing a secreted, constitutively-active form of TGF-β1 in astrocytes at modest levels develop age-related cerebrovascular abnormalities including thickening of the capillary basement membrane and cerebrovascular amyloid deposition. Nevertheless, these mice have better cognitive function than non-transgenic controls. Similar microvascular abnormalities are typical for AD and consistent with the observation that TGF-β1 mRNA levels in brains of AD cases correlate positively with vascular amyloid deposition.
TGF-β1 transgenic mice cross-bred with human amyloid precursor (hAPP) transgenic mice, develop synaptic degeneration and amyloid plaques in the brain parenchyma. Unexpectedly, a prominent reduction in plaque formation and overall Aβ accumulation was found in hAPP/TGF-β1 double transgenic compared with hAPP mice. Most of the remaining amyloid accumulated around cerebral blood vessels.
Increased levels of TGF-β1 reduced the number of plaques in human amyloid precursor protein (hAPP) mice by 75% and overall Aβ levels by 60%, compared to mice with normal levels of TGF-β1. Interestingly, TGF-β1 stimulated microglial cells to degrade synthetic Aβ peptide in culture. Because TGF-β1 also caused an activation of microglia in hAPP/TGF-β1 mice, these data suggest that at least some of the effects of TGF-β1 involve the activation of microglial phagocytosis. The need remains for more effective pharmaceutical compounds for treating and preventing stroke, heart disease, bone loss, cancer, multiple sclerosis, wound healing, inflammation, and neurodegenerative disorders, especially, but not limited to, Alzheimer's disease.